Rapamycin oximes

ABSTRACT

A compound of the structure ##STR1## wherein R 1  is ##STR2## R 2  is hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, arylalkyl, or Ar; 
     R 3  is hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, arylalkyl, or --CO 2  R 8  ; 
     R 4  is alkyl, alkenyl, alkynyl, trifluoromethyl, arylalkyl, Ar, aminoalkyl, thioalkyl, alkylthioalkyl, hydroxyalkyl, or --CO 2  R 8  ; 
     R 5  is hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, arylalkyl, At, or --CO 2  R 8  ; 
     R 6  is hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, arylalkyl, or Ar; 
     R 7  is alkyl, alkenyl, alkynyl, trifluoromethyl, arylalkyl, or Ar; 
     R 8  is hydrogen, alkyl, alkenyl, alkynyl, trifluoromethyl, arylalkyl, fluorenylmethyl, or 
     Ar; 
     Y is O or S; 
     X is ═N--O--(CH 2 ) f  --Z or ═N--O--Ar; 
     Z is hydrogen, alkenyl, alkynyl, alkoxy, cyano, fluoro, trifluoromethyl, --NR 5  R 6 , aryloxy, or Ar; 
     Ar is aryl which may be optionally mono-, di-, or tri- substituted; 
     a=0-4; 
     b=0-1; 
     c=0-4; 
     d=0-6; 
     e=0-6; and 
     f=0-6; 
     or a pharmaceutically acceptable salt thereof, with the proviso that when f is 0, Z is hydrogen and further provided that when R 3  or R 5  is --CO 2  R 8 , R 8  is not hydrogen which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.

BACKGROUND OF THE INVENTION

This invention relates to oximes of rapamycin and a method for usingthem for inducing immunosuppression, and in the treatment oftransplantation rejection, host vs. graft disease, autoimmune diseases,diseases of inflammation, adult T-cell leukemia/lymphoma, solid tumors,fungal infections, and hyperproliferative vascular disorders.

Rapamycin is a macrocyclic triene antibiotic produced by Streptomyceshygroscopicus, which was found to have antifungal activity, particularlyagainst Candida albicans, both in vitro and in vivo [C. Vezina et al.,J. Antibiot. 28, 721 (1975); S. N. Sehgal et al., J. Antibiot. 28,727(1975); H. A. Baker et al., J. Antibiot. 31,539 (1978); U.S. Pat. No.3,929,992; and U.S. Pat. No. 3,993,749].

Rapamycin alone (U.S. Pat. No. 4,885,171) or in combination withpicibanil (U.S. Pat. No. 4,401,653) has been shown to have antitumoractivity. R. Martel et al. [Can. J. Physiol. Pharmacol. 55, 48 (1977)]disclosed that rapamycin is effective in the experimental allergicencephalomyelitis model, a model for multiple sclerosis; in the adjuvantarthritis model, a model for rheumatoid arthritis; and effectivelyinhibited the formation of IgE-like antibodies.

The immunosuppressive effects of rapamycin have been disclosed in FASEB3, 3411 (1989). Cyclosporin A and FK-506, other macrocyclic molecules,also have been shown to be effective as immunosuppressive agents,therefore useful in preventing transplant rejection [FASEB 3, 3411(1989); FASEB 3, 5256 (1989); R. Y. Calne et al., Lancet 1183 (1978);and U.S. Pat. No. 5,100,899].

Rapamycin has also been shown to be useful in preventing or treatingsystemic lupus erythematosus [U.S. Pat. No. 5,078,999], pulmonaryinflammation [U.S. Pat. No. 5,080,899], insulin dependent diabetesmellitus [Fifth Int. Conf. Inflamm. Res. Assoc. 121 (Abstract), (1990)],smooth muscle cell proliferation and intimal thickening followingvascular injury [Morris, R. J. Heart Lung Transplant 11 (pt. 2): 197(1992)], adult T-cell leukemia/lymphoma [European Patent Application525,960 A1], and ocular inflammation [European Patent Application532,862 A1].

Mono- and diacylated derivatives of rapamycin (esterified at the 28 and43 positions) have been shown to be useful as antifungal agents (U.S.Pat. No. 4,316,885) and used to make water soluble aminoacyl prodrugs ofrapamycin (U.S. Pat. No. 4,650,803). Recently, the numbering conventionfor rapamycin has been changed; therefore according to ChemicalAbstracts nomenclature, the esters described above would be at the 31-and 42- positions. U.S. Pat. No. 5,023,264 discloses oximes of rapamycinuseful as immunosuppressive, antiinflammatory, and antifungal agents.U.S. Pat. No. 5,130,307 discloses aminoesters of rapamycin useful asimmunosuppressive, antiinflammatory, and antifungal agents. U.S. Pat.No. 5,221,670 discloses esters of rapamycin useful as immunosuppressive,antiinflammatory, antitumor, and antifungal agents.

DESCRIPTION OF THE INVENTION

This invention provides derivatives of rapamycin which are useful asimmunosuppressive, antiinflammatory, antifungal, antiproliferative, andantitumor agents having the structure ##STR3## wherein R¹ is ##STR4## R²is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms.alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, or Ar;

R³ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, or --CO₂ R⁸ ;

R⁴ is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms. alkynyl of2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbon atoms, Ar,aminoalkyl of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms,alkylthioalkyl of 2-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms,or --CO₂ R⁸ ;

R⁵ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, Ar, or --CO₂ R⁸ ;

R⁶ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, or Ar;

R⁷ is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbon atoms, orAr;

R⁸ is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms,alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, fluorenylmethyl, or Ar;

Y is O or S;

X is ═N--O--(CH₂)_(f) --Z or ═N--O--Ar;

Z is hydrogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,alkoxy of 1-6 carbon atoms, cyano, fluoro, trifluoromethyl, --NR⁵ R⁶,aryloxy, or Ar;

Ar is aryl which may be optionally mono-, di-, or tri- substituted witha group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro,carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy,amino, dialkylamino of 1-6 carbon atoms per alkyl group,dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms,--SO₃ H, --PO₃ H, and --CO₂ H;

a=0-4;

b=0-1;

c=0-4;

d=0-6;

e=0-6; and

f=0-6;

or a pharmaceutically acceptable salt thereof, with the proviso thatwhen f is 0, Z is hydrogen and further provided that when R³ or R⁵ is--CO₂ R⁸, R⁸ is not hydrogen.

The pharmaceutically acceptable salts are those derived from suchinorganic cations such as sodium, potassium, and the like; organic basessuch as: mono-, di-, and trialkyl amines of 1-6 carbon atoms, per alkylgroup and mono-, di-, and trihydroxyalkyl amines of 1-6 carbon atoms peralkyl group, and the like; and organic and inorganic acids as: acetic,lactic, citric, tartaric, succinic, maleic, malonic, gluconic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, and similarly known acceptable acids.

It is preferred that the aryl moiety of the Ar group or of the arylalkylor aryloxy groups is a phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl,quinoxalyl, thienyl, thionaphthyl, furyl, benzofuryl, benzodioxyl,benzoxazolyl, benzoisoxazolyl, indolyl, thiazolyl, isoxazolyl,pyrimidinyl, pyrazinyl, benzopyranyl, benz[b]thiophenolyl,benzimidazolyl, benzothiazolyl, benzodioxolyl, piperidyl, morpholinyl,piperazinyl, tetrahydrofuranyl, or pyrrolidinyl group which may beoptionally mono-, di-, or trisubstituted with a group selected fromalkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbonatoms, trifluoromethyl, amino, dialkylamino of 1-6 carbon atoms peralkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbonatoms, --SO₃ H, --PO₃ H, and --CO₂ H. It is more preferred that the arylmoiety is a phenyl group that may be optionally substituted as describedabove. The term alkyl of 1-6 carbon atoms includes both straight chainas well as branched carbon chains.

The oxime at the 27-position can exist in both the E and the Z forms;this disclosure covers both of these forms. When R¹ is an amino acid,the chiral center can contain either the R or S stereo configuration;this disclosure covers both enantiomers.

Of the compounds of this invention, preferred members are those in whichX is ═N--O--(CH₂)_(f) --Z; and those in which X is ═N--O--(CH₂)_(f) --Zand Z is hydrogen or cyano.

The compounds of this invention can be prepared by reacting the27-ketone with an appropriately substituted hydroxylamine to give the27-oxime by the route shown below. This route was also used in U.S. Pat.No. 5,023,264, which is hereby incorporated by reference. ##STR5##

The substituted hydroxylamines are either commercially available or canbe prepared by standard literature procedures as illustrated in Example1.

Having the rapamycin 27-oxime in hand, the 42-position can be acylatedwith a suitable acylating agent. For the compounds of this inventioncontaining an ester at the 42-position, the esterification can beaccomplished according to the methodology described in U.S. Pat. No.5,221,670, which is hereby incorporated by reference. The compounds ofthis invention which contain an aminoacyl moiety can be preparedaccording to the methodology disclosed in U.S. Pat. No. 5,130,307, whichis hereby incorporated by reference. The compounds of this inventionwhich contain a carbonate at the 42-position can be prepared accordingto the methodology described in U.S. patent application Ser. No.07/979,072, filed Oct. 19, 1992, which is hereby incorporated byreference. The above described methodology was used to prepare severalrepresentative compounds of this invention, as shown for the compoundsof Examples 1-9.

Alternatively, the compounds of this invention can be prepared by firstacylating the 42-position of rapamycin as described above, followed byconvening the 27 ketone to an oxime by the scheme described above. Thisroute was used to prepare the compounds of Examples 10 and 11.

When the 42-position of the 27-oximated rapamycin is acylated, mixturesof 31-acylated-27-oximated rapamycin and 31,42-bisacylated-27-oximatedrapamycin are also produced. These compounds can be separated andisolated by chromatography, and are considered pan of this disclosure.

The starting materials used to prepare the compounds of the inventionare commercially available or can be prepared by methods that aredisclosed in the literature.

This invention also covers analogous oximes of other rapamycins such as,but not limited to, 29-demethoxyrapamycin, [U.S. Pat. No. 4,375,464,32-demethoxyrapamycin under C.A. nomenclature]; rapamycin derivatives inwhich the double bonds in the 1-, 3-, and/or 5-positions have beenreduced [U.S. Pat. No. 5,023,262]; 29-desmethylrapamycin [U.S. Pat. No.5,093,339, 32-desmethylrapamycin under C.A. nomenclature];7,29-bisdesmethylrapamycin [U.S. Pat. No. 5,093,338,7,32-desmethylrapamycin under C.A. nomenclature]; and15-hydroxyrapamycin [U.S. Pat. No. 5,102,876]. The disclosures in theabove cited U.S. Patents are hereby incorporated by reference.

Immunosuppressive activity for representative compounds of thisinvention was evaluated in an in vitro standard pharmacological testprocedure to measure lymphocyte proliferation (LAF) and in an in vivostandard pharmacological test procedure which evaluated the survivaltime of a pinch skin graft.

The comitogen-induced thymocyte proliferation procedure (LAF) was usedas an in vitro measure of the immunosuppressive effects ofrepresentative compounds. Briefly, cells from the thymus of normalBALB/c mice are cultured for 72 hours with PHA and IL-1 and pulsed withtritiated thymidine during the last six hours. Cells are cultured withand without various concentrations of rapamycin, cyclosporin A, or testcompound. Cells are harvested and incorporated radioactivity isdetermined. Inhibition of lymphoproliferation is assessed as percentchange in counts per minute from nondrug treated controls. For eachcompound evaluated, rapamycin was also evaluated for the purpose ofcomparison. An IC₅₀ was obtained for each test compound as well as forrapamycin. When evaluated as a comparator for the representativecompounds of this invention, rapamycin had an IC₅₀ ranging from 0.4-5.1nM. The results obtained are provided as an IC₅₀.

Representative compounds of this invention were also evaluated in an invivo test procedure designed to determine the survival time of pinchskin graft from male BALB/c donors transplanted to male C₃ H(H-2K)recipients. The method is adapted from Billingham R. E. and Medawar P.B., J. Exp. Biol. 28:385-402, (1951 ). Briefly, a pinch skin graft fromthe donor was grafted on the dorsum of the recipient as a allograft, andan isograft was used as control in the same region. The recipients weretreated with either varying concentrations of test compoundsintraperitoneally or orally. Rapamycin was used as a test control.Untreated recipients serve as rejection control. The graft was monitoreddaily and observations were recorded until the graft became dry andformed a blackened scab. This was considered as the rejection day. Themean graft survival time (number of days±S.D.) of the drug treatmentgroup was compared with the control group. The following table shows theresults that were obtained. Results are expressed as the mean survivaltime in days. Untreated (control) pinch skin grafts are usually rejectedwithin 6-7 days. The results shown in Table I are based on a dose of 4mg/kg of test compound. A survival time of 12.0±1.7 days was obtainedfor rapamycin at 4 mg/kg.

The following table summarizes the results of representative compoundsof this invention in these two standard test procedures.

                  TABLE 1                                                         ______________________________________                                        EVALUATION OF IMMUNOSUPPRESSIVE ACTIVITY                                                    LAF       Skin Graft                                            Compound      IC.sub.50 (nM)                                                                          (days ± SD)                                        ______________________________________                                        Example 3     432                                                             Example 7     291                                                             Example 8     421                                                             Example 9     77                                                                            47                                                              Example 10    4.1       10.0 ± 0.2                                                                 11.2 ± 0.8                                         Example 11    372                                                                           321                                                             ______________________________________                                    

The results of these standard pharmacological test proceduresdemonstrate immunosuppressive activity both in vitro and in vivo for thecompounds of this invention. The results obtained in the LAF testprocedure indicates suppression of T-cell proliferation, therebydemonstrating the immunosuppressive activity of the compounds of thisinvention. As transplanted pinch skin grafts are typically rejectedwithin 6-7 days without the use of an immunosuppressive agent, theincreased survival time of the skin graft when treated with thecompounds of this invention further demonstrates their utility asimmunosuppressive agents.

Based on the results of these standard pharmacological test procedures,the compounds are useful in the treatment or prevention oftransplantation rejection such as kidney, heart, liver, lung, bonemarrow, pancreas (islet cells), cornea, small bowel, and skinallografts, and heart valve xenografts; in the treatment of autoimmunediseases such as lupus, rheumatoid arthritis, diabetes mellitus,myasthenia gravis, and multiple sclerosis; and diseases of inflammationsuch as psoriasis, dermatitis, eczema, seborrhea, inflammatory boweldisease, and eye uveitis.

Because of the activity profile obtained, the compounds of thisinvention also are considered to have antitumor, antifungal activities,and antiproliferative activities. The compounds of this inventiontherefore also useful in treating solid tumors, adult T-cellleukemia/lymphoma, fungal infections, and hyperproliferative vasculardiseases such as restenosis and atherosclerosis.

It is contemplated that when the compounds of this invention are used asan immunosuppressive or antiinflammatory agent, they can be administeredin conjunction with one or more other immunoregulatory agents. Suchother immunoregulatory agents include, but arc not limited toazathioprine, corticosteroids, such as prednisone andmethylprednisolone, cyclophosphamide, rapamycin, cyclosporin A, FK-506,OKT-3, and ATG. By combining the compounds of this invention with suchother drugs or agents for inducing immunosuppression or treatinginflammatory conditions, the lesser amounts of each of the agents amrequired to achieve the desired effect. The basis for such combinationtherapy was established by Stepkowski whose results showed that the useof a combination of rapamycin and cyclosporin A at subtherapeutic dosessignificantly prolonged heart allograft survival time. [TransplantationProc. 23: 507 (1991)].

The compounds of this invention provide a significant advantage overrapamycin, and the oximes and acyl derivatives of rapamycin in the prioran as they are substantially more stable toward degradative hydrolysisas shown for the compound of Example 10 in the table below. The tablebelow provides the half liter in 0.1M phosphate buffer (pH 7.4) at 37°C.

                  TABLE 2                                                         ______________________________________                                        STABILITY UNDER PHYSIOLOGICAL CONDITIONS                                                                  Half Life                                         Compound                    (hours)                                           ______________________________________                                        Example 10                  264                                               Rapamycin                   13                                                Rapamycin (Z)-27-(O-methoxime)                                                                            156                                               Rapamycin (E)-27-(O-methoxime)                                                                            59                                                Rapamycin 42-ester with (S)-5-tertbutoxy-4-tert-                                                          24                                                butoxycarbonylamino-5-oxo-pentanoic acid                                      ______________________________________                                    

The stability data in the table above shows that the compound of Example10 is significantly more stable toward degradation than rapamycin, orthe corresponding oxime or ester alone. The increased stability of thecompounds of this invention provide advantages in the formulation, andadministration of the compounds of this invention over the compounds ofthe prior art, as they are not readily subject to degradation underphysiological conditions.

As the compound of Example 3 was prepared via the compound of Example 2,the compound of Example 2 is useful as an intermediate in thepreparation of the compound of Example 3.

The compounds of this invention can be formulated neat or with apharmaceutical carder to a mammal in need thereof. The pharmaceuticalcarder may be solid or liquid.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarder having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carder can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carder for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. The compound can also be administered orallyeither in liquid or solid composition form.

The compounds of this invention may be administered rectally in the formof a conventional suppository. For administration by intranasal orintrabronchial inhalation or insufflation, the compounds of thisinvention may be formulated into an aqueous or partially aqueoussolution, which can then be utilized in the form of an aerosol. Thecompounds of this invention may also be administered transdermallythrough the use of a transdermal patch containing the active compoundand a carrier that is inert to the active compound, is non toxic to theskin, and allows delivery of the agent for systemic absorption into theblood stream via the skin. The carrier may take any number of forms suchas creams and ointments, pastes, gels, and occlusive devices. The creamsand ointments may be viscous liquid or semisolid emulsions of either theoil-in-water or water-in-oil type. Pastes comprised of absorptivepowders dispersed in petroleum or hydrophilic petroleum containing theactive ingredient may also be suitable. A variety of occlusive devicesmay be used to release the active ingredient into the blood stream suchas a semipermiable membrane covering a reservoir containing the activeingredient with or without a carrier, or a matrix containing the activeingredient. Other occlusive devices are known in the literature.

In addition, the compounds of this invention may be employed as asolution, cream, or lotion by formulation with pharmaceuticallyacceptable vehicles containing 0.1-5 percent, preferably 2%, of activecompound which may be administered to a fungally affected area.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Based on the results obtained inthe standard pharmacological test procedures, projected daily dosages ofactive compound would be 0.1 μg/kg-100 mg/kg, preferably between0,001-25 mg/kg, and more preferably between 0.01-5 mg/kg. Treatment willgenerally be initiated with small dosages less than the optimum dose ofthe compound. Thereafter the dosage is increased until the optimumeffect under the circumstances is reached; precise dosages for oral,parenteral, nasal, or intrabronchial administration will be determinedby the administering physician based on experience with the individualsubject treated. Preferably, the pharmaceutical composition is in unitdosage form, e.g. as tablets or capsules. In such form, the compositionis sub-divided in unit dose containing appropriate quantities of theactive ingredient; the unit dosage forms can be packaged compositions,for example, packeted powders, vials, ampoules, prefilled syringes orsachets containing liquids. The unit dosage form can be, for example, acapsule or tablet itself, or it can be the appropriate number of anysuch compositions in package form.

The following examples illustrate the preparation of representativecompounds of this invention.

EXAMPLE 1

Cyanomethoxyamine Hydrochloride

To a mixture of 16.8 g (0.1 mol) N-hydroxyphthalimide and 12.7 g (0.11mol) tert-BuOK in 150 mL DMF under stirring was added cyanomethylchloride (7.8 g, 0.1 mol). Discoloration of the reaction mixtureoccurred in 10 min. After 24 h of stirring at room temperature themixture was poured into 750 mL of cold H₂ O. Precipitate was filteredoff and dried under vacuum in the presence of anhydrous CaSO₄ to yieldabout 10 g (50%) of cyanomethoxyphthalimide. To a solution of 10 g (0.05mol) cyanomethoxyphthalimide in 50 mL THF was added dropwise at roomtemperature during 2 h a solution of 2.5 mL (0.05 mol) hydrazine-hydrate(100%) in 10 mL MeOH. After additional stirring for 2 h the mixture wasacidified under ice-cooling with 25 mL of 2M solution (0.05 mol) HCl andthe resulting mixture was stirred at this temperature for 30 min. Theinsoluble material was filtered off, filtrate adjusted to pH 7 with 2MNaOH. The product was then extracted 4 times with EtOAc, the combinedorganics were washed with brine, and dried over anhydrous Na₂ SO₄. Thesolution was concentrated in vacuo, the residue was dissolved in etherand treated with an excess of dry hydrogen chloride. The title compound,a precipitate, was filtered off and dried under vacuum in the presenceof anhydrous CaSO₄.

EXAMPLE 2

Rapamycin 27-(O-cyanomethyloxime) E and Z Isomers

To a solution of rapamycin (1.0 g, 1.1 mmol) in MeOH (15 mL) was addedNaOAc (0.240 g, 2.86 mmol) followed by cyanomethoxyamine hydrochloride(0.320 g, 2.86 mmol). The mixture was degassed, purged with nitrogen,and stirred at 23° C. for 72 h. The reaction mixture was then quenchedwith H₂ O. The organic layer and aqueous layer were separated. Theaqueous layer was extracted three times with EtOAc. The organic layerswere combined, washed with brine, and dried over Na₂ SO₄. The solutionwas filtered and concentrated in vacuo to afford a pale yellow powder.TLC analysis (10% hexane/EtOAc) indicated two major components werepresent. The isomers were separated by HPLC (35% H₂ O/MeCN through aDynamax C₁₈ column, 15 mL/min).

Analysis of one of the fractions indicated that it wasrapamycin-27-(O-cyanomethyloxime) Z-isomer (477 mg, 45% overall yield).Spectroscopic data confirmed the structure. ¹ H NMR (400 MHz, DMSO-d₆) δ5.9-6.5 (m, 4H),4.95 (m, 2H), 3.9 (m, 1H). MS (neg. FAB): 967[M]⁻,590.2, 546.3, 167.1. Anal. calcd. for C₅₃ H₈₁ N₃ O₁₃.H₂ O: C 64.54%, H8.27%, N 4.26%; Found: C 61.30%, H 7.98%, N 3.68%. IR (KBr, cm⁻¹): 3440,2930, 1750, 1640, 1450.

Analysis of the other fraction indicated that it was the E-isomer (159mg, 15% overall yield). Spectroscopic data confirmed the structure. ¹ HNMR (400 MHz, DMSO-d₆) δ 6.0-6.6 (m, 4H),4.87 (s, 1H), 4.65 (s, 1H), 3.3(m, 1H). MS (neg. FAB): 967[M]⁻, 590.2, 546.3, 167.1. Anal. calcd. forC₅₃ H₈₁ N₃ O₁₃.H₂ O: C 64.54%, H 8.27%, N 4.26%; Found: C 64.59%, H8.43%, N 3.88%. IR (KBr, cm⁻¹): 3430, 2920, 1740, 1640, 1450.

EXAMPLE 3

Rapamycin (Z)-27-O-(cyanomethyl)-oxime, 42-ester withN-(tert-butoxycarbonyl)-α-O-(tert-butyl)-L-glutamic Acid

To a solution of rapamycin-O-27-cyanomethoxime (0.48 g, 0.5 mmol) in drydichloromethane (7.5 mL) was added N-Boc glutamic acid t-butyl ester(0.18 g, 0.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.120 g, mmol) and DMAP (0.006 g, 0.05 mmol). The mixturewas stirred for 4 days. The mixture was diluted with H₂ O (20 mL) andEtOAc (50 mL). After vigorous shaking the layers were separated, aqueouslayer was extracted 3 times with EtOAc, combined organics washed withbrine and dried over anhydrous Na₂ SO₄. The solvent was evaporated invacuo to afford pale-yellow material. TLC analysis (50% hexane/EtOAc)indicated four major components were present. The oxime E- and Z-isomerswere separated by HPLC (30% H₂ O/MeCN through a Dynamax 2" phenylcolumn, 20 mL/min).

Analysis of one of the fractions indicated that it was the titlecompound (170 mg, 27% overall yield). Spectroscopic data confirmed thestructure. ¹ H NMR (400 MHz, DMSO-d₆) δ 5.9-6.5 (m, 4H), 4.85-4.95 (m,2H), 4.62 (m, 1H 1.4 (m, 18H). MS (neg. FAB): 1252.4[M]⁻, 590.3, 167.1.Anal. calcd. for C₆₇ H₁₀₄ N₄ O₁₈ : C 63.39%, H 8.26%, N 4.41%; Found: C63.91%, H 8.51%, N 4.11%. IR (KBr, cm⁻¹): 3420, 2950, 1740, 1650, 1450,1370.

EXAMPLE 4

Rapamycin (Z)-27-O-(cyanomethyl)-oxime, 31-ester withN-(tert-butoxycarbonyl)-α-O-(tert-butyl)-L-glutamic Acid

The title compound was prepared according to the procedure of Example 3,and was separated by HPLC (30% H₂ O/MeCN through a Dynamax 2" phenylcolumn, 20 mL/min). Analysis of one of the fractions indicated that itwas the title compound (70 mg, 11% overall yield). Spectroscopic dataconfirmed the structure. ¹ H NMR (400 MHz, DMSO-d₆) δ 6.0-6.5 (m, 4H),5.05 (m, 1H),4.81-4.91 (m, 2H), 1.4 (m, 18H). MS (neg. FAB): 1252.4[M]⁻,590.3, 167.1. Anal. calcd. for C₆₇ H₁₀₄ N₄ O₁₈ : C 63.39%, H 8.26%, N4.41%; Found: C 63.77%, H 8.35%, N 4.23%. IR (KBr, cm⁻¹): 3400, 2930,1740, 1650, 1450,1370.

EXAMPLE 5

Rapamycin (Z)-27-O-(cyanomethyl)-oxime, 31-ester withN-(tert-butoxycarbonyl)-α-O-(tert-butyl)-L-glutamic Acid

The title compound was prepared according to the procedure of Example 3,and was separated by HPLC (30% H₂ O/MeCN through a Dynamax 2" phenylcolumn, 20 mL/min). Analysis of one of the fractions indicated that itwas the title compound (120 mg, 17% overall yield). Spectroscopic dataconfirmed the structure. ¹ H NMR (400 MHz, DMSO-d₆) δ 6.0-6.5 (m, 4H),5.05 (m, 1H), 4.83-4.91 (m, 2H), 4.96 (m, 1H), 1.4 (m, 36H). MS (neg.FAB): 1537.8[M]⁻, 1251.3, 590.2, 168.1. Anal. calcd. for C₈₁ H₁₂₇ N₅ O₂₃: C 63.22%, H 8.32%, N 4.55%; Found: C 63.36%, H 8.64%, N 4.23%. IR(KBr, cm⁻¹): 3400, 2950, 1740, 1650, 1500, 1460,1370.

EXAMPLE 6

Rapamycin 27-(O-methoxime) E and Z Isomers

To a solution of rapamycin (1.57 g, 1.717 mmol) in MeOH (50 mL) wasadded NaOAc (0.2453 g, 2.99 mmol), followed by methoxyaminehydrochloride (0.2457 g, 2.94 mmol). The mixture was degassed, purgedwith nitrogen, and stirred vigorously at 23° C. for 48 h. The reactionmixture was then quenched with H₂ O. The organic layer and aqueous layerwere separated. The aqueous layer was extracted three times with EtOAc.The organic layers were combined, washed with brine, and dried over Na₂SO₄. The solution was filtered and concentrated in vacuo to afford apale yellow foam. TLC analysis (25% hexane/EtOAc) indicated two majorcomponents were present. The product mixture was separated by HPLC (30%H₂ O/MeCN through a Dynamax 2" phenyl column, 20 mL/min) to afford twofractions along with minor contamination of rapamycin. The rapamycinimpurity was removed by HPLC (35% H₂ O/MeCN, Dynamax 1" column, 5mL/min).

One fraction was determined to be rapamycin (Z)-27-(O-methoxime) (824.4mg, 50.97% overall yield). ¹ H NMR (400 MHz, DMSO-d₆) δ 6.42 (m, 2H),6.1-6.25 (m, 2H), 5.95 (d, 1H), 5.5 (dd, 1H), 5.18 (d, 1H), 4.95 (d,1H), 4.78 (broad d, 1H), 3.75 (s, 3H). MS (neg. FAB): 942.4 [M]⁻, 590.2,546.3, 167.1. Anal. calcd. for C₅₂ H₈₂ N₂ O₁₃.H₂ O: C 64.96%, H 8.80%, N2.91%; Found: C 65.35%, H 8.92%, N 2.82%. IR (KBr, cm⁻¹): 3430, 2930,1730, 1645, 1450.

The other fraction was determined to be rapamycin (E)-27-(O-methoxime)(275 mg, 17% overall yield). ¹ H NMR (400 MHz, DMSO-d₆) δ 5.9-6.5 (m.4H) 5.2 (d, 1H), 3.75 (s, 3H). MS (neg. FAB): 942.4 [M]⁻, 590.2, 546.3,167.1. Anal. calcd. for C₅₂ H₈₂ N₂ O₁₃.H₂ O: C 64.96%, H 8.80%, N 2.91%;Found: C 65.27%, H 8.68%, N 2.53%. IR (KBr, cm⁻¹): 3430, 2930, 1730,1645, 1450.

EXAMPLE 7

Rapamycin (Z)-27-(O-methoxime), 42-ester with 2-N,N-dimethylglycine

To a solution of rapamycin-27-(O-methoxime) (0.48 g, 0.5 mmol, mixtureof isomers) in dry dichloromethane (7.5 mL) was added dimethylglycinehydrochloride (0.063 g, 0.6 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.120 g,0.6 mmol) and DMAP (0.012 g, 0.1 mmol). The mixture was stirred for 4days. Then the mixture was diluted with H₂ O (20 mL) and EtOAc (50 mL).After vigorous shaking the layers were separated, the aqueous layer wasextracted 3 times with EtOAc, the combined organics washed with brine,and dried over anhydrous Na₂ SO₄. Solvent was evaporated in vacuo toafford pale-yellow material. TLC analysis (50% hexane/EtOAc) indicatedthat four major components were present. The oxime E- and Z-isomers wereinitially separated by HPLC on Dynamax 2" C₁₈ column (35% H₂ O/MeCN, 20mL/min) and finally fraction, containing 42-ester was repurified onDynamax 2" phenyl column (40% H₂ O/MeCN, 20 mL/min). Analysis of majorfraction indicated that it was the title compound. Isolation gave about100 mg (20% overall yield). Spectroscopic data confirmed the structure.¹ H NMR (400 MHz, DMSO-d₆) δ 5.9-6.4 (m, 4H), 3.74 (s, 3H), 2.24 (m,6H). MS (neg. FAB): 1027[M]⁻, 590.3, 167.1. Anal. calcd. for C₅₆ H₈₉ N₃O₁₄. H₂ O: C 64.41%, H 8.72%, N 4.09%; Found: C 64.28%, H 8.77%, N4.02%. IR (KBr, cm⁻¹): 3400, 2940, 1780, 1650, 1450.

EXAMPLE 8

Rapamycin (Z)-27-(O-methoxime), 42-ester with(5-benzyloxycarbonylmethoxy) acetic acid

To a solution of rapamycin 27-(O-methoxime) (mixture of isomers) (0.38g, 0.40 mmol) in dichloromethane (20 mL) was added5-benzyloxycarbonylmethoxyacetic acid (0.22 g, 0.982 mmol) portionwise,DMAP (0.0568 g, 0.465 mmol), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1562 g,0.815 mmol). The reaction mixture was degassed, purged with nitrogen,and stirred at room temperature for 30 h. The reaction was quenched withH₂ O, and the organic and aqueous layers were separated. The aqueouslayer was extracted three times with EtOAc. The organic layers werecombined, washed with brine, and dried over Na₂ SO₄. The solution wasfiltered and concentrated in vacuo to afford a pale yellow foam. TLCanalysis (25% hexane/EtOAc) indicated at least three compounds. Themixture was separated and purified by HPLC (30% H₂ O/MeCN, Dynamax 2"phenyl column, 20 mL/min) to give the title compound (76.5 mg, 16.6%overall yield). ¹ H NMR (400 MHz, DMSO-d₆ ) δ 7.35 (s, 5H), 5.18 (s,2H), 4.28 (s, 2H), 4.22 (s, 2H), 3.75 (s, 3H). MS (neg. FAB): 1148.5[M]⁻, 924.5, 590.3, 223.2. Anal. calcd. for C₆₃ H₉₂ N₂ O₁₇.H₂ O: C64.84%, H 8.06%, N 2.40%; Found: C 65.14%, H 8.29%, N 2.36%. IR (KBr,cm⁻¹): 3400, 2925, 1740, 1625, 1460.

EXAMPLE 9

Rapamycin (E)-27-(O-methoxime), 42-ester with (4-nitrophenoxy)carbonicacid

To a solution of rapamycin 27-(O-methoxime) (mixture of isomers) (1.54g, 1.63 mmol) in THF:H₂ O (50 mL, 1:1) at 0° C. was added pyridine(0,264 mL, 3.26 mmol) portionwise, DMAP (0.5649 g, 4.62 mmol), and4-nitrophenyl chloroformate (0.5078 g, 2.51 mmol). The reaction mixturewas degassed, purged with nitrogen, stirred at 0° C. for 3 h, warmed upto room temperature and stirred or 48 h. The reaction was quenched withH₂ O, and the organic and aqueous layers were separated. The aqueouslayer was extracted three times with EtOAc. The organic layers werecombined, washed with brine, and dried over Na₂ SO₄. The solution wasfiltered and concentrated in vacuo to afford a pale yellow foam. TLCanalysis (50% hexane/EtOAc) indicated at least three compounds. Theproduct mixture was separated and purified by HPLC (30% H₂ O/MeCN,Dynamax 2" phenyl column, 20 mL/min), to give the title compound (87.9mg, 4.86% overall yield). ¹ H NMR (400 MHz, DMSO-d₆) δ 8.3 (d, 2H), 7.55(d, 2H), 6.42 (d, 1H), 6.05 (d, 1H), 5.48 (q, 1H), 5.1 (d, 1H), 4.65 (m,1H), 4.25 (d, 1H), 3.68 (s, 3H). MS (neg. FAB): 1107.2 [M]⁻, 590.2,546.3. Anal. calcd. for C₅₉ H₈₅ N₃ O₁₇.H₂ O: C 62.93%, H 7.73%, N 3.73%;Found: C 62.99%, H 7.70%, N 3.93%. IR (KBr, cm⁻¹): 3450, 2945, 1775,1755, 1645, 1620, 1530, 1460.

EXAMPLE 10

Rapamycin (Z)-27-(O-methoxime), 42-ester with(S)-5-tertbutoxy-4-tertbutoxycarbonylamino-5-oxo-pentanoic acid and

EXAMPLE 11

Rapamycin (E)-27-(O-methoxime), 42-ester with(S)-5-tertbutoxy-4-tertbutoxycarbonylamino-5-oxo-pentanoic acid

A solution of the rapamycin 42-ester with(S)-5-tertbutoxy-4-tertbutoxycarbonylamino-5-oxo-pentanoic acid (U.S.Pat. No. 5,130,307, Example 6) (1.0 g, 0.83 mmol), methoxylaminehydrochloride (0.069 g, 0.83 mmol) and sodium acetate (0.069 g, 0.83mmol) in CH₃ OH (8 mL) were stirred at ambient temperature under anatmosphere of nitrogen overnight. The reaction was filtered and thefiltrate was evaporated to give 1.0 g of a light yellow solid (mixtureof E and Z isomers in a 4:1 ratio respectively). The crude material waspurified by HPLC (Dynamax 60A Phenyl 21×250 mm column, 85%acetonitrile-15% H₂ O, 5 mL/min flow rate, and UV 280 nm detection) togive 0.6 g (white solid, 59%) of the major Z isomer and 0.08 g of theminor E isomer.

The spectral data for the Z-isomer are as follows: ¹ H-NMR (400 MHz,CDCl₃): δ 1.437 (s, 9H, CO₂ But), 1.465 (s, 9H, CO₂ But), 3.137 (s, 3H,CH₃ O), 3.30 (s, 3H, CH₃ O), 3.384 (s, 3H, CH₃ O), 3.80 (s, 1H, NOCH₃),4.65 (m, 1H, 42-CH); ¹³ C-NMR (CDCl₃, 100 MHz): δ 217.2, 191.99, 172.39,168.759, 166.87, 158.09, 155.47, 140.94, 135.26, 134.65, 134.21, 134.14,130.13, 129.96, 129.90, 128.51, 125.86, 98.51; MS (negative ion FAB):1227 [M--H]--. Anal Calc'd for C₆₆ H₁₀₅ N₃ O₁₈ ·2.0H₂ O: C, 62.69; H,8.69; N, 3.32 Found: C, 62.73; H, 8.58; N, 3.22

The spectral data for the E-isomer are as follows: ¹ H-NMR (400 MHz,CDCl₃): δ 1.437 (s, 9H, CO₂ But), 1.465 (s, 9H, CO₂ But), 3.174 (s, 3H,CH₃ O), 3.307 (s, 3H, CH₃ O), 3.389 (s, 3H, CH₃ O), 3.84 (s, 1H, NOCH₃),4.66 (m, 1H, 42-CH); ¹³ C-NMR (CDCl₃, MHz): δ 211.67, 191.08, 172.42,168.64, 167.10, 158.60, 138.07, 134.81, 133.64, 132.85, 129.80, 129.22,128.35, 126.75, 98.35; MS (negative ion FAB): 1227[M--H]--, 1197, 590,546.

What is claimed is:
 1. A compound of the structure ##STR6## wherein R¹is ##STR7## R² is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of7-10 carbon atoms, or Ar;R³ is hydrogen, alkyl of 1-6 carbon atoms,alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,trifluoromethyl, arylalkyl of 7-10 carbon atoms, or --CO₂ R⁸ ; R⁴ isalkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbon atoms, Ar,aminoalkyl of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms,alkylthioalkyl of 2-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms,or --CO₂ R⁸ ; R⁵ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of7-10 carbon atoms, Ar, or --CO₂ R⁸ ; R⁶ is hydrogen, alkyl of 1-6 carbonatoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,trifluoromethyl, arylalkyl of 7-10 carbon atoms, or Ar; R⁷ is alkyl of1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbonatoms, trifluoromethyl, arylalkyl of 7-10 carbon atoms, or Ar; R⁸ ishydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms,alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, fluorenylmethyl, or Ar; Y is O or S; X is ═N--O--(CH₂)_(f) --Z or═N--O--Ar; Z is hydrogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, cyano, fluoro,trifluoromethyl, --NR⁵ R⁶, aryloxy, or Ar; Ar is aryl which may beoptionally mono-, di-, or tri- substituted with a group selected fromalkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbonatoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms,hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms,alkylthio of 1-6 carbon atoms, --SO₃ H, --PO₃ H, and --CO₂ H;a=0-4; b=0-1; c=0-4; d=0-6; e=0-6; and f=0-6;or a pharmaceutically acceptablesalt thereof, with the proviso that when f is 0, Z is hydrogen andfurther provided that when R³ or R⁵ is --CO₂ R⁸, R⁸ is not hydrogen. 2.The compound according to claim 1 wherein X is ═N--O--(CH₂)_(f) --Z or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 2 wherein Z is hydrogen or cyano or a pharmaceutically acceptablesalt thereof.
 4. The compound according to claim 1 which is rapamycin(Z)-27-O-(cyanomethyl)-oxime, 42-ester withN-(tert-butoxycarbonyl)-α-O-(tert-butyl)-L-glutamic acid or apharmaceutically acceptable salt thereof.
 5. The compound according toclaim 1 which is rapamycin (Z)-27-(O-methoxime), 42-ester with2-N,N-dimethylglycine or a pharmaceutically acceptable salt thereof. 6.The compound according to claim 1 which is rapamycin(Z)-27-(O-methoxime), 42-ester with (5-benzyloxycarbonylmethoxy) aceticacid or a pharmaceutically acceptable salt thereof.
 7. The compoundaccording to claim 1 which is rapamycin (E)-27-(O-methoxime), 42-esterwith (4-nitrophenoxy)carbonic acid or a pharmaceutically acceptable saltthereof.
 8. The compound according to claim 1 which is rapamycin(Z)-27-(O-methoxime), 42-ester with(S)-5-tert-butoxy-4-tertbutoxycarbonylamino-5-oxo-pentanoic acid or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1 which is rapamycin (E)-27-(O-methoxime), 42-ester with(S)-5-tert-butoxy-4-tert-butoxycarbonylamino-5-oxo-pentanoic acid or apharmaceutically acceptable salt thereof.
 10. A method of inducingimmunosuppression in a mammal in need thereof by administering to saidmammal an immunosuppressive amount of a compound having the structure##STR8## wherein R¹ is ##STR9## R² is hydrogen, alkyl of 1-6 carbonatoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,trifluoromethyl, arylalkyl of 7-10 carbon atoms, or Ar;R³ is hydrogen,alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbon atoms, or --CO₂R⁸ ; R⁴ is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, Ar, aminoalkyl of 1-6 carbon atoms, thioalkyl of 1-6 carbonatoms, alkylthioalkyl of 2-12 carbon atoms, hydroxyalkyl of 1-6 carbonatoms, or --CO₂ R⁸ ; R⁵ is hydrogen, alkyl of 1-6 carbon atoms, alkenylof 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, trifluoromethyl,arylalkyl of 7-10 carbon atoms, Ar, or --CO₂ R⁸ ; R⁶ is hydrogen, alkylof 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbonatoms, trifluoromethyl, arylalkyl of 7-10 carbon atoms, or Ar; R⁷ isalkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbon atoms, or Ar; R⁸is hydrogen, alkyl of 1-8 carbon atoms, alkenyl of 2-7 carbon atoms,alkynyl of 2-7 carbon atoms, trifluoromethyl, arylalkyl of 7-10 carbonatoms, fluorenylmethyl, or Ar; Y is O or S; X is ═N--O--(CH₂)_(f) --Z or═N--O--Ar; Z is hydrogen, alkenyl of 2-7 carbon atoms, alkynyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, cyano, fluoro,trifluoromethyl, --NR⁵ R⁶, aryloxy, or Ar; Ar is aryl which may beoptionally mono-, di-, or tri- substituted with a group selected fromalkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbonatoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms,hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms,alkylthio of 1-6 carbon atoms, --SO₃ H, --PO₃ H, and --CO₂ H;a=0-4;b=0-1; c=0-4; d=0-6; e=0-6; and f=0-6;or a pharmaceutically acceptablesalt thereof, with the proviso that when f is 0, Z is hydrogen andfurther provided that when R³ or R⁵ is --CO₂ R⁸, R⁸ is not hydrogen.